BACKGROUND: Immuno-oncology (IO) drugs are essential for treating various cancer types; however, safety concerns persist in older patients. Although the incidence of immune-related adverse events (irAEs) is similar among age groups, higher rates of hospitalization or discontinuation of IO therapy have been reported in older patients. Limited research exists on IO drug safety and risk factors in older adults. Our investigation aimed to assess the incidence of irAEs and identify the potential risk factors associated with their development. METHODS: This retrospective analysis reviewed the clinical data extracted from the medical records of patients aged > 80 years who underwent IO treatment at our institution. Univariate and multivariate analyses were performed to assess the incidence of irAEs. RESULTS: Our study included 181 patients (median age: 82 years, range: 80-94), mostly men (73%), with a performance status of 0-1 in 87% of the cases; 64% received IO monotherapy. irAEs occurred in 35% of patients, contributing to IO therapy discontinuation in 19%. Our analysis highlighted increased body mass index, eosinophil counts, and albumin levels in patients with irAEs. Eosinophil count emerged as a significant risk factor for any grade irAEs, particularly Grade 3 or higher, with a cutoff of 118 (/µL). The group with eosinophil counts > 118 had a higher frequency of irAEs, and Grade 3 or higher events than the group with counts ≤ 118. CONCLUSION: IO therapy is a safe treatment option for patients > 80 years old. Furthermore, patients with elevated eosinophil counts at treatment initiation should be cautiously managed.
Immune Checkpoint Inhibitors , Neoplasms , Humans , Retrospective Studies , Male , Female , Aged, 80 and over , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/drug therapy , Neoplasms/immunology , Risk Factors , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/etiology , Incidence
Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.
Although phase III randomized controlled trials (RCTs) represent the most robust statistical approach for answering clinical questions, they require massive expenditures in terms of time, labor, and funding. Ancillary and supplementary analyses using RCTs are sometimes conducted as alternative approaches to answering clinical questions, but the available integrated databases of RCTs are limited. In this background, the Colorectal Cancer Study Group (CCSG) of the Japan Clinical Oncology Group (JCOG) established a database of ancillary studies integrating four phase III RCTs (JCOG0212, JCOG0404, JCOG0910 and JCOG1006) conducted by the CCSG to investigate specific clinicopathological factors in pStage II/III colorectal cancer (JCOG2310A). This database will be updated by adding another clinical trial data and accelerating several analyses that are clinically relevant in the management of localized colorectal cancer. This study describes the details of this database and planned and ongoing analyses as an initiative of JCOG cOlorectal Young investigators (JOY).
Clinical Trials, Phase III as Topic , Colorectal Neoplasms , Databases, Factual , Humans , Colorectal Neoplasms/therapy , Colorectal Neoplasms/pathology , Randomized Controlled Trials as Topic , Japan , Neoplasm Staging
BACKGROUND: Data regarding treatment sequence for vulnerable patients with metastatic colorectal cancer (mCRC) in a real-world setting are lacking. OBJECTIVE: We aimed to assess treatment outcomes in second-line or later chemotherapy for vulnerable patients with mCRC in a real-world setting. PATIENTS AND METHODS: Vulnerable patients with mCRC who received less intensive treatment ('vulnerable') regimens, i.e. fluoropyrimidines with or without biologics (FP), reduced-dose doublet regimens with or without biologics (Doublet), and anti-epidermal growth factor receptor monotherapy (Anti-EGFR), as first-line therapy between June 2015 and December 2018 were retrospectively reviewed. RESULTS: A total of 210 patients from 15 hospitals were analyzed. The median age was 78 years (range 28-90), and 44 patients (21%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2. In the entire population, the median time to treatment failure (TTF) and overall survival (OS) were 7.6 and 21.4 months, respectively. Following the failure of first-line therapy in 195 patients, 74 (38%), 24 (12%), and 13 (7%) patients received vulnerable regimens, full-dose doublet regimens with or without biologics, and other regimens, respectively, whereas 84 (43%) received best supportive care (BSC). In patients receiving vulnerable regimens as second-line therapy, the median TTF and OS were 4.4 and 13.7 months, respectively, while response rate and disease control rate were 18% and 62%, respectively. In 84 patients who received BSC, the median OS was 3.5 months. CONCLUSIONS: Second-line chemotherapy for vulnerable patients with mCRC showed clinically meaningful outcomes; however, few patients received second-line therapy, and survival among patients who received BSC was dismal.
Biological Products , Colonic Neoplasms , Humans , Adult , Middle Aged , Aged , Aged, 80 and over , Retrospective Studies , Time-to-Treatment
PURPOSE: Circulating tumor DNA (ctDNA) genotyping on the basis of next-generation sequencing (NGS) may guide targeted therapy for metastatic colorectal cancer (mCRC). However, the validity of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment and the efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA results remains unclear. PATIENTS AND METHODS: The performance of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment was compared with that of a validated polymerase chain reaction-based tissue testing in patients with mCRC enrolled in the GOZILA study, a nationwide plasma genotyping study. The primary end points were concordance rate, sensitivity, and specificity. The efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA were also evaluated. RESULTS: In 212 eligible patients, the concordance rate, sensitivity, and specificity were 92.9% (95% CI, 88.6 to 96.0), 88.7% (95% CI, 81.1 to 94.0), and 97.2% (95% CI, 92.0 to 99.4) for RAS and 96.2% (95% CI, 92.7 to 98.4), 88.0% (95% CI, 68.8 to 97.5), and 97.3% (95% CI, 93.9 to 99.1) for BRAF V600E, respectively. In patients with a ctDNA fraction of ≥1.0%, sensitivity rose to 97.5% (95% CI, 91.2 to 99.7) and 100% (95% CI, 80.5 to 100.0) for RAS and BRAF V600E mutations, respectively. In addition to a low ctDNA fraction, previous chemotherapy, lung and peritoneal metastases, and interval between dates of tissue and blood collection were associated with discordance. The progression-free survival of anti-EGFR therapy and BRAF-targeted treatment was 12.9 months (95% CI, 8.1 to 18.5) and 3.7 (95% CI, 1.3 to not evaluated) months, respectively, for matched patients with RAS/BRAF V600E results by ctDNA. CONCLUSION: ctDNA genotyping effectively detected RAS/BRAF mutations, especially with sufficient ctDNA shedding. Clinical outcomes support ctDNA genotyping for determining the use of anti-EGFR and BRAF-targeted therapies in patients with mCRC.
Colonic Neoplasms , Colorectal Neoplasms , Rectal Neoplasms , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Proto-Oncogene Proteins B-raf/genetics , Genotype , Japan , Mutation
Although nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) has been used to treat first-line resistant unresectable pancreatic cancer, the efficacy and safety data among the elderly remain limited. We retrospectively analyzed clinical outcomes among elderly patients. Patients treated with nal-IRI+5-FU/LV were assigned to the elderly (≥75 years) and non-elderly (<75 years) groups. Herein, 85 patients received nal-IRI+5-FU/LV, with 32 assigned to the elderly group. Patient characteristics in the elderly and non-elderly groups were as follows: age: 78.5 (75-88)/71 (48-74), male: 17/32 (53%/60%), performance status (ECOG) 0:9/20 (28%/38%), nal-IRI+5-FU/LV in second line: 23/24 (72%/45%), respectively. A significantly high number of elderly patients exhibited aggravated kidney and hepatic functions. Median overall survival (OS) and progression-free survival (PFS) in the elderly group vs. non-elderly group were 9.4 months vs. 9.9 months (hazard ratio (HR) 1.51, 95% confidence interval (CI) 0.85-2.67, p = 0.16) and 3.4 months vs. 3.7 months (HR 1.41, 95% CI 0.86-2.32, p = 0.17). Both groups exhibited a similar incidence of efficacy and adverse events. There were no significant differences in OS and PFS between groups. We analyzed the C-reactive protein/albumin ratio (CAR) and neutrophil/lymphocyte ratio (NLR) as indicators that could determine eligibility for nal-IRI+5-FU/LV. The median CAR and NLR scores in the ineligible group were 1.17 and 4.23 (p < 0.001 and p = 0.018, respectively). Elderly patients with worse CAR and NLR score could be deemed ineligible for nal-IRI+5-FU/LV.
BACKGROUND: Characteristics and prognoses of patients with occult metastases (OM) of pancreatic ductal adenocarcinoma (PDAC) compared with radiologically defined metastases (RM) have been rarely reported. OBJECTIVE: We aimed to clarify the prognosis of OM compared with RM and to establish a treatment strategy for PDAC patients with OM. METHODS: This single-institution, retrospective study evaluated patients with unresectable PDAC between 2008 and 2018. OM was defined as abdominal metastasis that was detected by staging laparoscopy or open laparotomy but not in the initial assessment of radiological images. RESULTS: OM and RM were identified in 135 and 112 patients, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS), neutrophil to lymphocyte ratio (NLR), tumor diameter, and rate of local unresectability were significantly lower in the OM group. Median overall survival (OS) of OM was significantly better than that of RM (13.0 vs 8.9 months, p < 0.001). In multivariate analysis of OS, ECOG PS ≥ 1 (HR 1.64, p = 0.009), NLR ≥5 (HR 1.97, p = 0.004), carbohydrate antigen (CA) 19-9 ≥1000 (HR 1.68, p = 0.001), tumor diameter ≥40 mm (HR 1.40, p = 0.027), conversion surgery (HR 0.12, p < 0.001), and multiple lines of chemotherapy (HR 0.38, p < 0.001) were independent predictors. However, type of metastasis (OM vs RM) not an independent predictor (HR 1.10, p = 0.590). CONCLUSION: The prognosis of PDAC with OM was relatively better than that with RM, but general and nutritional statuses, primary tumor size and CA19-9, conversion surgery and multiple lines of chemotherapy were independent predictors but not tumor burden.
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Pancreatic Neoplasms , Humans , Retrospective Studies , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/therapy , Prognosis , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/secondary , Pancreatic Neoplasms
BACKGROUND: In Japan, nivolumab administration is the standard treatment for patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy. We determined if inflammatory prognostic factors are useful in patients with ESCC treated with nivolumab monotherapy. METHODS: The clinical data of patients with ESCC treated with nivolumab monotherapy as the second- or later-line treatment were retrospectively analyzed. Neutrophil/lymphocyte, platelet/lymphocyte, and C-reactive protein/albumin ratios (CAR); prognostic index; and prognostic nutritional index were investigated. Cut-off values for each factor were determined according to overall survival using time-dependent receiver operating characteristic curves. RESULTS: During January 2017-June 2021, 93 consecutive patients with ESCC were enrolled from five institutions (median age, 70 years; male, 77%). With a median follow-up period of 9.1 (range, 1.0-34.7) months, the median overall and progression-free survival were 12.8 (95% confidence interval [CI], 9.0-16.6) and 4.0 (95% CI, 2.6-5.4) months, respectively. Of five inflammatory prognostic factors, the cut-off value for CAR was 0.62; prognosis was significantly longer in those with CAR < 0.62 (hazard ratio, 0.39; 95% CI, 0.22-0.67; p = 0.001). CONCLUSIONS: Inflammatory prognostic factors were useful in predicting prognosis for ESCC patients pretreated with nivolumab, especially for those with CAR < 0.62, suggesting that CAR adequately reflects prognosis.
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Aged , Humans , Male , Chronic Disease , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/chemically induced , Neoplasm Recurrence, Local , Nivolumab/therapeutic use , Prognosis , Retrospective Studies , Female
Background: Surgical resection for liver-only synchronous metastases of pancreatic ductal adenocarcinoma remains controversial. We investigated the role of conversion surgery in patients with a favorable response to systemic chemotherapy. Methods: Patients (n=49) were diagnosed liver-only synchronous metastases using staging laparoscopy or open laparotomy between 2007 and 2022. Clinical outcomes were retrospectively compared among patients who underwent conversion surgery (n=10), upfront surgery with or without short-term neoadjuvant chemotherapy (UpS/short NAC) for oligometastases and occult metastases limited to the liver (n=8), and chemotherapy only for resectable or borderline resectable disease with occult liver-only metastases (n=31). The surgical indication of conversion surgery was fixed as the ABC criteria, namely, Anatomical objective response of disappearance of liver metastases on imaging studies, Biological response of CA19-9 level decrease to ≤150 U/mL, and Conditional response of surgical fitness. In addition to the above ABC criteria, tumor disappearance at the liver was repeatedly confirmed using staging laparoscopy (laparoscopic response; L), and metabolic complete responses were confirmed using positron emission tomography-computed tomography (CT) (metabolic response; M). Results: Median survival time from initial treatment was 9.9 months [95% confidence interval (CI): 8.3-10.9] in the chemotherapy group, 10.4 months (95% CI: 6.6-17.8) in the UpS/short NAC group, and 36.7 months (95% CI: 19.0-84.8) in the conversion surgery group (conversion surgery vs. UpS/short NAC, P=0.002; conversion surgery vs. chemotherapy, P<0.001; UpS/short NAC vs. chemotherapy, P=0.554). One patient in the UpS/short NAC group and three in the conversion surgery group achieved 5-year survival. Among them, two patients with initially multiple liver metastases (≥10) in the conversion surgery group survived beyond 5 years. Only conversion surgery was a significant independent prognostic factor in a total cohort (hazard ratio; 0.173, P=0.002). Conclusions: Conversion surgery, but not UpS/short NAC, may enhance survival in patients with synchronous liver metastases and favorably anatomical, biological and conditional responses to systemic chemotherapy.
The BRAF V600E mutation accounts for approximately 5% of colorectal cancer (CRC) cases and is an extremely poor prognostic factor. However, there are no clear recommendations regarding first-line therapy for patients with early recurrent BRAF V600E-mutated CRC, during or after adjuvant chemotherapy. Recently, a novel combination of encorafenib, binimetinib and cetuximab, showed a higher response rate than standard chemotherapy in patients with BRAF V600E-mutated CRC. Here we describe our plan for the TRESBIEN study (OGSG 2101), which is an open-label, multicenter, single-arm, phase II study designed to evaluate whether encorafenib, binimetinib and cetuximab are effective for patients with early recurrent BRAF V600E-mutated colorectal cancer, during or after adjuvant chemotherapy. The planned number of subjects is 25.
An ongoing study to evaluate encorafenib, binimetinib and cetuximab for people with early recurrent BRAF V600E-mutated colorectal cancer. BRAF V600E-mutated colorectal cancer (CRC) is a type of cancer caused by change (mutation) in a gene called BRAF. It is one of the most difficult types of CRC to treat because currently available drugs do not effectively treat the disease. Recently, two novel treatments, encorafenib and cetuximab, have been approved for use together in several countries for the treatment of advanced or metastatic BRAF V600E-mutated CRC. In Japan, these drugs are also approved to be given with another treatment called binimetinib, an approach called triplet therapy. This article describes the ongoing TRESBIEN study that is looking at how effective and how safe triplet therapy is for the treatment of people with early recurrent BRAF V600E-mutated CRC, during or after they have additional (adjuvant) chemotherapy. This study is ongoing, and the researchers are currently recruiting new participants. TRESBIEN will evaluate the percentage of participants whose tumors shrink with triplet therapy. The study will also look at any side effects. Clinical Trial Registration: jRCTs051210152 (ClinicalTrials.gov) (Japan Registry of Clinical Trials https://jrct.niph.go.jp/search?language=en&page=1).
Colorectal Neoplasms , Proto-Oncogene Proteins B-raf , Humans , Cetuximab/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Clinical Trials, Phase II as Topic , Multicenter Studies as Topic
Background: A trial with trifluridine/tipiracil (FTD/TPI) versus placebo in patients with heavily pretreated metastatic gastric cancer showed that FTD/TPI is effective with manageable toxicity in these patients. However, real-world data on the effects of FTD/TPI in patients with advanced gastric cancer (AGC) are limited. Methods: We retrospectively collected and analyzed the clinicopathological data of patients with AGC who received FTD/TPI monotherapy at our institutions (Kobe City Medical Center General Hospital, Osaka Red Cross Hospital, Himeji Red Cross Hospital, and Kansai Medical University Hospital) between September 2019 and July 2021. Tumor responses were evaluated based on the Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method. Results: A total of 53 patients were included in the study. The median age was 70 (range, 37-85) years; 39 patients (74%) were men; the numbers of patients with Eastern Cooperative Oncology Group performance status scores of 0, 1, and 2 were 10 (19%), 39 (74%), and 4 (8%), respectively; and 27 patients (51%) had diffuse-type histology. A total of 29 patients (56%) had ascites. Prior nivolumab therapy was administered to 49 patients (92%). The response rate and disease control rate (DCR) were 2% and 35%, respectively. The median progression-free survival was 2.4 months, and OS was 5.8 months. Patients with ascites exhibited significantly shorter OS (8.6 vs 4.7 months, P = .0291) than those without ascites, and DCR (54% vs 18%, P = .0055) was significantly worse in patients with ascites. There was no significant difference in the frequency of adverse events of grade 3 or higher between patients with and without ascites. Conclusion: In a real-world setting, FTD/TPI has similar effectiveness as late-line chemotherapy for patients with AGC, including those who previously had received nivolumab.
BACKGROUND: The decision to perform surgery is complicated by the presence of multifocal (MF) intraductal papillary mucinous neoplasms (IPMNs), which are characterized by two or more cysts located in different areas of the pancreas. OBJECTIVES: We aimed to establish a suitable treatment strategy and surgical indications in patients with MF-IPMNs. METHODS: This single-center retrospective study included patients with IPMNs who underwent pancreatic resection from 2006 to 2020. Patients with distant metastasis and patients with IPMNs of the main pancreatic duct were excluded from the analysis. RESULTS: After excluding 22 patients, 194 patients were included. One hundred thirteen patients (58.2%) had unifocal IPMNs, while 81 patients (41.8%) had MF-IPMNs. There were no significant differences in the 5-year disease-specific survival (DSS) rate (92.3% vs. 92.4%, p = 0.976) and the 5-year disease-free survival rate (88.6% vs. 86.5%, p = 0.461). The multivariate analysis identified high-risk stigmata, invasive carcinoma, and lymph node metastasis as independent predictors of DSS. The presence of cystic lesions in the pancreatic remnant was not a predictor of survival. Even in the MF-IPMN group, there were no significant differences in DSS when stratified by procedure (total pancreatectomy vs. segmental pancreatectomy, p = 0.268) or presence of cystic lesions in the pancreatic remnant (p = 0.476). The multivariate analysis identified lymph node metastasis as an independent predictor of DSS in the MF-IPMN group. CONCLUSIONS: In patients with MF-IPMNs, each cyst should be evaluated individually for the presence of features associated with malignancy.
Carcinoma, Pancreatic Ductal , Pancreatic Intraductal Neoplasms , Pancreatic Neoplasms , Humans , Pancreatectomy/methods , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Intraductal Neoplasms/surgery , Retrospective Studies , Lymphatic Metastasis , Pancreatic Neoplasms/pathology
Trastuzumab deruxtecan (T-DXd) has shown promising efficacy against HER2-positive advanced gastric cancer (AGC). However, data on its real-world efficacy in AGC patients are insufficient, and the predictive marker of T-DXd is unclear. In this multi-center retrospective study, we collected clinical information of 18 patients with HER2-positive AGC who received T-DXd after intolerant or refractory responses to at least two prior regimens and analyzed predictive factors. The median age was 71 years (range: 51-85), 13 men were included, and ECOG performance status (PS): 0/1/2/3 was 9/6/2/1. A total of 11 patients (61%) received prior immune checkpoint inhibitors (ICIs), 14 patients were HER2 3+, and 4 patients were HER2 2+/FISH positive. The median trastuzumab (Tmab)-free interval was 7.7 months (range: 2.8-28.6). The overall response rate was 41%, and the disease control rate was 76%. Median progression-free survival (PFS) was 3.9 months (95% CI: 2.6-6.5), and median overall survival (OS) was 6.1 months (95% CI: 3.7-9.4). PFS (6.5 vs. 2.9 months, p = 0.0292) and OS (9.2 vs. 3.7 months, p = 0.0819) were longer in patients who received prior ICIs than in those who had not. PFS (6.5 vs. 3.4 months, p = 0.0249) and OS (9.4 vs. 5.7 months, p = 0.0426) were longer in patients with an 8 month or longer Tmab-free interval. In patients with ascites, PFS (6.5 vs. 2.75 months, p = 0.0139) and OS (9.4 vs. 3.9 months, p = 0.0460) were shorter. T-DXd showed promising efficacy in HER2-positive AGC patients in a real-world setting. Pre-administration of ICIs and a sufficient Tmab-free interval may be predictive factors of T-DXd efficacy.
Background: Intraperitoneal chemotherapy using paclitaxel (i.p.-PTX) is expected to be a new therapeutic strategy for patients with pancreatic ductal adenocarcinoma (PDAC) and peritoneal dissemination. We evaluated the survival benefit of i.p.-PTX compared with standard systemic chemotherapy. Methods: Clinical data of 101 consecutive PDAC patients with peritoneal dissemination between 2007 and 2018 were analyzed. All patients were determined to have no other sites of distant organ metastasis to the lung, bone, or liver on contrast-enhanced CT imaging. Patients underwent staging laparoscopy or open laparotomy to confirm pathological evidence of peritoneal dissemination, and to exclude occult liver metastasis. Survival curves were estimated using the Kaplan−Meier method, and differences were compared using the log-rank test. Results: Forty-three patients were treated with i.p.-PTX (i.p.-PTX group) and forty-nine patients received standard systemic chemotherapy (Ctrl group). Nine patients did not receive any treatment (BSC group). The median survival time (MST) in the i.p.-PTX group was significantly longer than that in the Ctrl group (17.9 months vs. 10.2 months, p = 0.006). Negative peritoneal washing cytology was observed in 24 out of 43 patients in the i.p.-PTX group. The i.p.-PTX group tended to have a higher proportion of clinical responses than the Ctrl group (30% vs. 18%, p = 0.183). Conversion surgery was performed in 10 patients in the i.p.-PTX group and 2 patients in the Ctrl group after confirming disappearance of peritoneal dissemination with staging laparoscopy or open laparotomy (p = 0.005). The MST in patients who underwent surgical resection was significantly longer than that in patients who did not (27.4 months vs. 11.3 months; p < 0.0001). Conclusion: i.p.-PTX therapy provided improved survival in PDAC patients with peritoneal dissemination, and conversion surgery enhanced it in patients with favorable responses to chemotherapy. i.p.-PTX might become one of the treatment options to PDAC patients with peritoneal dissemination.
MEK inhibitors are among the most successful molecularly targeted agents used as cancer therapeutics. However, to treat cancer more efficiently, resistance to MEK inhibitor-induced cell death must be overcome. Although previous genetic approaches based on comprehensive gene expression analysis or RNAi libraries led to the discovery of factors involved in intrinsic resistance to MEK inhibitors, a feasible combined treatment with the MEK inhibitor has not yet been developed. Here, we show that a chemoproteoinformatics approach identifies ligands overcoming the resistance to cell death induced by MEK inhibition as well as the target molecule conferring this resistance. First, we used natural products, perillyl alcohol and sesaminol, which induced cell death in combination with the MEK inhibitor trametinib, as chemical probes, and identified ribosomal protein S5 (RPS5) as their common target protein. Consistently, trametinib induced cell death in RPS5-depleted cancer cells via upregulation of the apoptotic proteins BIM and PUMA. Using molecular docking and molecular dynamics (MD) simulations, we then screened FDA- and EMA-approved drugs for RPS5-binding ligands and found that acetylsalicylic acid (ASA, also known as aspirin) directly bound to RPS5, resulting in upregulation of BIM and PUMA and induction of cell death in combination with trametinib. Our chemoproteoinformatics approach demonstrates that RPS5 confers resistance to MEK inhibitor-induced cell death, and that aspirin could be repurposed to sensitize cells to MEK inhibition by binding to RPS5.
Preoperative chemotherapy is efficacious in several cancers. However, it is not an established treatment for locally advanced colon cancer, particularly cases with microsatellite instability-high (MSI-H)/deficient mismatch repair. Herein, we report a case of pathological complete response of MSI-H clinical T4b ascending colon cancer to preoperative treatment with pembrolizumab. A 78-year-old man was diagnosed with ascending colon cancer that invaded into the iliacus muscle and enlarged regional lymph nodes. The tumor was classified as T4bN1bM0 stage IIIC according to the 8th Union for International Cancer Control guidelines, with MSI-H status. Based on our initial diagnosis, this tumor could not be resected completely. Thus, the patient underwent preoperative therapy with CAPOX (capecitabine and oxaliplatin combination) plus bevacizumab. After 4 cycles of preoperative CAPOX/bevacizumab, we observed tumor reduction corresponding to a partial response based on the Response Evaluation Criteria in Solid Tumors criteria. Nevertheless, tumor invasion of the iliacus muscle persisted. Since oxaliplatin-induced peripheral sensory neuropathy was observed, we discontinued treatment with oxaliplatin and changed the regimen to pembrolizumab in anticipation of the therapeutic effect of this immune checkpoint inhibitor against MSI-H tumors. After 2 cycles of therapy with pembrolizumab (200 mg/body on day 1 every 3 weeks), there was drastic tumor regression. In addition, computed tomography indicated that all lymph node metastases had disappeared. Therefore, the patient underwent laparoscopic right hemicolectomy with D3 lymph node dissection. Analysis of the resected specimen showed pathological complete response.
Medication support applications(apps)have been introduced to support oral anti-cancer drug management for outpatients with gastrointestinal cancer. It has been suggested that remote support using medication support apps contributes to improving the quality of life through adverse event management as well as medication management. However, it was evident that elderly patients could not install the apps due to barriers related to the network environments and device operations and medical problems such as information management and securing human resources.
Mobile Applications , Aged , Humans , Outpatients , Quality of Life
BACKGROUND: RAS/BRAFV600E mutations are the most remarkable oncogenic driver mutations in colorectal cancer (CRC) and play an important role in treatment selection. No data are available regarding the clinical and prognostic features of patients with detailed RAS/BRAFV600E-mutant metastatic CRC (mCRC) in Japan. METHODS: A total of 152 chemotherapy-naïve patients with mCRC were included in this study between August 2018 and July 2019. Tumor samples were collected, and RAS/BRAFV600E status was investigated. RAS/BRAFV600E status was examined using a MEBGEN RASKET-B kit and polymerase chain reaction reverse sequence-specific oligonucleotide method. RESULTS: RAS/BRAFV600E mutations were detected in 54% of cases (KRAS codon 12, 26%; KRAS codon 13, 17%; KRAS non-Exon2, 5%; NRAS, 5%; and BRAFV600E, 7%). BRAFV600E-mutant CRC mainly existed in the right colon, whereas KRAS non-Exon2 and NRAS-mutant CRC was predominantly present in the left colon. KRAS non-Exon2 and NRAS-mutant CRC were associated with shorter survival time than RAS wild-type CRC (hazard ratio [HR], 2.26; 95% confidence interval [CI], 0.64-8.03; p = 0.19; HR, 2.42; 95% CI, 0.68-8.61; p = 0.16) and significantly shorter overall survival than KRAS Exon2-mutant CRC (HR, 3.88; 95% CI, 0.92-16.3; p = 0.04; HR, 4.80; 95% CI, 1.14-20.2; p = 0.02). CONCLUSIONS: In our multicenter study, the findings elucidated the clinical and prognostic features of patients with detailed RAS/BRAFV600E-mutant mCRC in Japan.
Colorectal Neoplasms/genetics , GTP Phosphohydrolases/genetics , Membrane Proteins/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Prognosis , Young Adult
BACKGROUND: Carboplatin is a key drug for ovarian cancer. However, it sometimes induces hypersensitivity reactions (HSRs) that result in the discontinuation of the treatment. Although various desensitization protocols have been reported in previous retrospective studies, a limited number of prospective studies have analyzed these protocols. METHODS: Patients with platinum-sensitive relapsed ovarian cancer who experienced carboplatin-induced HSRs were treated with diluted solutions of 1/1000, 1/100, 1/10 and an undiluted solution of carboplatin over a 1-h period. If no HSRs occurred within the first two cycles, a short protocol regimen over a 30-min period per solution was followed. The primary endpoint was treatment completion rate. RESULTS: Between May 2015 and September 2018, 21 patients were enrolled from two institutions. One patient experienced platinum-sensitive recurrence after the desensitization protocol; thus, 22 sessions were analyzed. Epinephrine use, treatment-related death, and intensive care unit (ICU) admissions did not occur. The median number of desensitization cycles was 6 (range 1-6). Two sessions were discontinued early because of grade 2 dysgeusia and grade 2 malaise. Treatment in two (9.1%) patients was discontinued because of HSR development. The treatment completion rate was 90.9%. Six (27.3%) sessions met the criteria for transition to the short protocol regimen. In 14 (63.6%) sessions, HSRs were observed during infusion of the undiluted solution. The median progression-free survival and overall survival were 14.8 and 23.8 months, respectively. CONCLUSION: This 4-step, 2-h carboplatin desensitization protocol is safe and feasible. Patients require careful monitoring with a rapid response to HSRs, especially during the administration of undiluted solutions.
